Serine proteases are a group of endopeptidase enzymes which have a serine amino acid in their active center. Representative serine proteases include trypsin, thrombin, and plasmin related to blood coagulation and the fibrinolysis system (Chem. Pharm. Bull., 41(1):117 (1993)). Additionally, C1r and C1s in the complement system are serine proteases and provide a critical and multifaceted defense system in the host defense against infection. Constituting about 10% of the globulins in normal serum, the complement system is composed of many different proteins that are important in the immune system's response to foreign antigens. The complement system becomes activated when its primary components are cleaved and the products alone or with other proteins activate additional complement proteins resulting in a proteolytic cascade. Following activation, the complement cascade can increase vascular permeability, promote chemotaxis by phagocyte recognition, or kill microorganisms directly by lysis. Complement activation products are also involved in the adaptive immune responses that lead to antibody production (Current Opinion in Immunology, 5:83 (1993)).
Alzheimer's disease (AD) is the most common degenerative dementia affecting primarily the elderly population. The disease is characterized by the decline of multiple cognitive functions and a progressive loss of neurons in the central nervous system. Deposition of beta-amyloid peptide has also been associated with AD. Over the last decade, a number of investigators have noted that AD brains contain many of the classical markers of immunemediated damage. These include elevated numbers of microglia cells (these are believed to be an endogenous CNS form of the peripheral macrophage) and astrocytes. Of particular importance, complement proteins have been immunohistochemically detected in the AD brain and they most often appear associated with beta-amyloid containing pathological structures known as senile plaques (Proc. Natl. Acad. Sci. USA, 89:10016 (1992), Brain Research, 601:88 (1993), Age, 16(2):51 (1993)).
These initial observations which suggest the existence of an inflammatory component in the neurodegeneration observed in AD has been extended to the clinic. A small clinical study using the nonsteroidal antiinflammatory drug, indomethacin, indicated that indomethacin significantly slowed the progression of the disease (Neurology, 43(8):1609 (1993)). A larger study with indomethacin is presently ongoing. In addition, a study examining age of onset among 50 elderly twin pairs with onsets of AD separated by three or more years, suggested that antiinflammatory drugs may prevent or delay the initial onset of AD symptoms (Neurology, 44:227 (1994)).
U.S. Pat. No. 4,657,893 covers 2-amino-4H-3,1-benzoxazin-4-ones of formula ##STR1## and the pharmaceutically acceptable esters and salts thereof, wherein: R.sub.1 is hydrogen or lower alkyl;
R.sub.2 and R.sub.3 are each independently hydrogen, halogen, lower alkyl, hydroxy, lower alkoxy, lower thioalkyl, --NO.sub.2, --N(R').sub.2, --NR'COR', --NHCON(R').sub.2, or --NHCOOR', PA1 with the proviso that at least one of R.sub.1, R.sub.2, and R.sub.3 is not hydrogen when X is NHR or NR'COR"; and PA1 X is a radical chosen from the group consisting of: ##STR2## in which: R is lower alkyl, lower alkenyl, lower alkynyl, optionally substituted lower cycloalkyl, or optionally substituted phenyl lower alkyl; PA1 each R' is independently hydrogen or lower alkyl, or lower alkenyl or lower alkynyl where the unsaturated bond is at least one carbon removed from the O or N atom; PA1 each R" is independently R, lower alkoxy, NHR', or AOR'; and PA1 A is an amino acid residue, or a peptide of 2 to 3 amino acid residues. PA1 a is an integer of 1 to 4; PA1 A is a bond, or alkylene having 1 to 8 carbon atoms; PA1 R is hydrogen, phenyl, imidazolyl, or cycloalkyl having 3 to 6 carbon atoms, wherein the phenyl, imidazolyl, or cycloalkyl ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of lower alkyl having 1 to 4 carbon atoms, lower alkoxy having 1 to 4 carbon atoms, --N(R.sub.1).sub.2, --NO2, halo, or lower alkylthio having 1 to 4 carbon atoms, and PA1 each R' is independently selected from the group consisting of hydroxy, benzyloxy, lower alkyl having 1 to 6 atoms, lower alkenyl having 2 to 6 carbon atoms, lower alkoxy having 1 to 6 carbon atoms, lower alkylthio or halo-lower alkyl having 1 to 6 carbon atoms, halo, --NO.sub.2, --N(R.sub.1).sub.2, --NR.sub.1 CO.sub.2 R.sub.2, --NR.sub.1 COR.sub.2, and --NR.sub.1 C(O)N(R.sub.1).sub.2, PA1 in which PA1 A is an alkylene group if R is hydrogen, or a pharmaceutically acceptable acid addition salt thereof. PA1 R.sub.1 and R.sub.2 together form a cyclopentyl, cyclohexyl, or phenyl ring fused to the ring to which they are attached; PA1 n is an integer of from 0 to 1; PA1 R.sub.3 is hydrogen, methyl, or ethyl when n is 0; and PA1 R.sub.3 is alkyl of from 1 to 8 carbons or phenyl when n is 1; PA1 R.sub.4 is phenyl mono- or disubstituted at the ortho position(s) by chlorine, bromine, iodine, or trifluoromethoxy when n is 0; PA1 R.sub.4 is phenyl, phenyl substituted by 1 to 2 groups selected from fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, trifluoromethyl, unsubstituted or alkyl substituted guanidino or amidino when n=1; PA1 R.sub.4 is heteroaryl when n=1; and PA1 R.sub.4 is ##STR12## wherein m is an integer of from 2 to 6; and n is 0 or 1; X is oxygen or sulfur. PA1 R.sub.1 and R.sub.2 are each independently hydrogen, halogen, alkyl of from 1 to 6 carbon atoms, nitro, trifluoromethyl, guanidino, amidino, or R.sub.1 and R.sub.2 together form a cyclopentyl, cyclohexyl, or phenyl ring fused to the ring to which they are attached; PA1 n is 0; PA1 R.sub.3 is hydrogen, methyl, or ethyl; PA1 R.sub.4 is 2-chlorophenyl, 2-bromophenyl, 2-iodophenyl, 2-trifluoromethoxyphenyl, 2,6-dichlorophenyl, 2,6-diidophenyl, unsubstituted or substituted guanidino- or amidino-phenyl, ##STR13## and X is oxygen or sulfur. PA1 R.sub.1 and R.sub.2 are each independently hydrogen, 7-methyl, 6- or 7-chloro, 7-nitro or 7-trifluoromethyl, or R.sub.1 and R.sub.2 together form 6,7-benzo; PA1 n is 0; PA1 R.sub.3 is hydrogen or methyl; and PA1 R.sub.4 is 2-chlorophenyl, 2-bromophenyl, 2-iodophenyl, 2,6-dichlorophenyl, or 2-trifluoromethoxy. PA1 R.sub.1 and R.sub.2 are each hydrogen, methyl, amidino, or guanidino; PA1 n is 1; PA1 R.sub.3 is methyl or ethyl; PA1 R.sub.4 is phenyl, phenyl substituted by from 1 to 2 substituents selected from fluoro, chloro, bromo, iodo, alkyl, alkylthio, trifluoromethyl, amidino, guanidino, or R.sub.4 is heteroaryl. PA1 R.sub.1 and R.sub.2 are each independently hydrogen, methyl, 6- or 7-amidino, or 6- or 7-guanidino; PA1 n is 1; PA1 R.sub.3 is methyl or ethyl; PA1 R.sub.4 is phenyl, 2-iodophenyl, 2-bromophenyl, 2-thiomethylphenyl, 3-thienyl, 2-trifluoromethylphenyl, 3-amidinophenyl, 4-amidinophenyl, 3-guanidinophenyl, 4-guanidinophenyl, ##STR14## wherein m is an integer of from 2 to 5. PA1 2-(2-Chloro-phenylamino)-benzo[d][1,3]oxazin-4-one; PA1 2-(2-Bromo-phenylamino)-benzo[d][1,3]oxazin-4-one; PA1 2-(2-Iodo-phenylamino)-benzo[d][1,3]oxazin-4-one; PA1 2-(2-Trifluoromethoxy-phenylamino)-benzo[d][1,3]oxazin-4-one; PA1 2-(2,6-Dichloro-phenylamino)-benzo[d][1,3]oxazin-4-one; PA1 2-[Methyl-(2-iodo-phenylamino]benzo[d][1,3]oxazin-4-one; PA1 2-(2-Iodo-phenylamino)-naphtho[2,3-d][1,3]oxazin-4-one; PA1 2-Iodo-N-methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-benzamide; PA1 2-Bromo-N-methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-benzamide; PA1 N-Methyl-2-methylsulfanyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-benzamide; PA1 N-Methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-2-trifluoromethyl-benzamide; PA1 N-Methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)benzamide; PA1 2-Iodo-N-methyl-N-(6-methyl-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-benzamide; PA1 7-Chloro-2-(2-iodo-phenylamino)-benzo[d][1,3]oxazin-4-one; PA1 6-Chloro-2-(2-iodo-phenylamino)-benzo[d][1,3]oxazin-4-one; PA1 2-(2-Iodo-phenylamino)-7-methyl-benzo[d][1,3]oxazin-4-one; PA1 2-(2-Iodo-phenylamino)-7-nitro-benzo[d][1,3]oxazin-4-one; PA1 2-(2-Iodo-phenylamino)-7-trifluoromethyl-benzo[d][1,3]-oxazin-4-one; PA1 6,7-Dichloro-2-(2-iodo-phenylamino)-benzo[d][1,3]oxazin-4-one; PA1 Thiophene-3-carboxylic acid methyl-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-amide; PA1 3-Guanidino-N-methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-propionamide; PA1 4-Guanidino-N-methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-butyramide; PA1 4-Carbamimidoyl-N-methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-butyramide; PA1 5-Carbamimidoyl-pentanoic acid methyl-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-amide; PA1 N-(7-Guanidino-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-N-methyl-benzamide; PA1 N-(7-Carbamimidoyl-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-N-methyl-benzamide; PA1 N-(6-Guanidino-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-N-methyl-benzamide; PA1 N-(6-Carbamimidoyl-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-N-methyl-benzamide; PA1 4-Guanidino-N-methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-benzamide; PA1 3-Guanidino-N-methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-benzamide; PA1 4-Carbamimidoyl-N-methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-benzamide; PA1 3-Carbamimidoyl-N-methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-benzamide; PA1 N-{4-[Methyl-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)amino]-phenyl}-guanidine; PA1 N-{3-[Methyl-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)amino]-phenyl}-guanidine; PA1 4-[Methyl-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)amino]-benzamidine; PA1 3-[Methyl-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)amino]-benzamidine; PA1 Thiophene-3-carboxylic acid methyl-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-amide; PA1 N-(5-Chloro-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-2-iodo-N-methyl-benzamide; PA1 2-(2-Chloro-phenylamino)-7-methyl-benzo[d][1,3]oxazin-4-one; PA1 2-Iodo-N-methyl-N-(7-methyl-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-benzamide; PA1 6,7-Difluoro-2-(2-iodo-phenylamino)-benzo[d][1,3]oxazin-4-one; PA1 7-Fluoro-2-(2-iodo-phenylamino)-benzo[d][1,3]oxazin-4-one; PA1 6,7-Dichloro-2-(2-chloro-phenylamino)-benzo[d][1,3]oxazin-4-one; PA1 2-(2-Iodo-phenylamino)-7-trifluoromethyl-benzo[d][1,3]oxazin-4-one; PA1 N-(6,7-Dichloro-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-2-iodo-N-methyl-benzamid e; PA1 7-Chloro-2-(2,6-dichloro-phenylamino)-benzo[d][1,3]oxazin-4-one; PA1 2-o-Tolylamino-benzo[d][1,3]oxazin-4-one; PA1 2-(2-Chloro-phenylamino)-7-nitro-benzo[d][1,3]oxazin-4-one; PA1 2-(2,6-Dichloro-phenylamino)-7-trifluoromethylbenzo[d][1,3]oxazin-4-one; PA1 Furan-2-carboxylic acid methyl-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-amide; PA1 Naphthalene-1-carboxylic acid methyl-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-amide; PA1 N-Methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)nicotinamide; PA1 4-Butyl-N-methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-benzamide; PA1 4-Methoxy-N-methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-benzamide; and PA1 4-Cyano-N-methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-benzamide. PA1 2-[(2-Iodo-phenylamino]-benzo[d][1,3]oxazin-4-one; PA1 2-(2,6-Dichloro-phenylamino)-benzo[d][1,3]oxazin-4-one; PA1 7-Chloro-2-(2-iodo-phenylamino)-benzo[d][1,3]oxazin-4-one; PA1 6,7-Dichloro-2-(2-iodo-phenylamino)-benzo[d][1,3]oxazin-4-one; PA1 2-(2-Iodo-phenylamino)-7-nitro-benzo[d][1,3]oxazin-4-one; PA1 2-(2-Iodo-phenylamino)-7-trifluoromethylbenzo[d][1,3]oxazin-4-one; PA1 2-[Methyl-(2-iodo-phenylamino]-benzo[d][1,3]oxazin-4-one; PA1 N-Methyl-2-iodo-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-benzamide; PA1 N-Methyl-2-trifluoromethyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-benzamide; PA1 N-Methyl-2-methylsulfanyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-benzamide; PA1 3-Guanidino-N-methyl-N-(4-oxo-4H-benzo[d][1,3]thiazin-2-yl)-propionamide; PA1 4-Guanidino-N-methyl-N-(4-oxo-4H-benzo[d][1,3]thiazin-2-yl)-butyramide; PA1 4-Carbamimidoyl-N-methyl-N-(4-oxo-4H-benzo[d][1,3]thiazin-2-yl)-butyramide; PA1 5-Carbamimidoyl-pentanoic acid methyl-(4-oxo-4H-benzo[d][1,3]thiazin-2-yl)-amide; PA1 4-Carbamimidoyl-N-methyl-N-(4-oxo-4H-benzo[d][1,3]thiazin-2-yl)-benzamide; PA1 4-Guanidino-N-methyl-N-(4-oxo-4H-benzo[d][1,3]thiazin-2-yl)-benzamide; PA1 3-Carbamimidoyl-N-methyl-N-(4-oxo-4H-benzo[d][1,3]thiazin-2-yl)-benzamide; PA1 3-Guanidino-N-methyl-N-(4-oxo-4H-benzo[d][1,3]thiazin-2-yl)-benzamide; PA1 N-(7-Guanidino-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-2-iodo-N-methyl-benzamide ; PA1 N-(7-Guanidino-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-N-methyl-2-trifluoromethy l-benzamide; PA1 N-(7-Guanidino-4-oxo-4H-benzo[d][1,3]thiazin-2-yl)-N-methyl-benzamide; PA1 N-(7-Carbamimidoyl-4-oxo-4H-benzo[d][1,3]thiazin-2-yl)-N-methyl-benzamide; PA1 N-(6-Guanidino-4-oxo-4H-benzo[d][1,3]thiazin-2-yl)-N-methyl-benzamide; and PA1 N-(6-Carbamimidoyl-4-oxo-4H-benzo[d][1,3]thiazin-2-yl)-N-methyl-benzamide. PA1 Heptanoic acid methyl-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-amide; PA1 Cyclohexanecarboxylic acid methyl-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-amide; PA1 Heptanoic acid ethyl-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-amide; PA1 Undecanoic acid methyl-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-amide; PA1 N-Methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-3-phenyl-propionamide; PA1 N-Methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)acetamide; PA1 Hexanoic acid methyl-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-amide; PA1 Octanoic acid methyl-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-amide; PA1 6-Bromo-hexanoic acid methyl-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-amide; PA1 N-Methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)propionamide; PA1 Pentanoic acid methyl-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-amide; PA1 Heptanoic acid (4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-amide; PA1 Heptanoic acid (4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-phenyl-amide; PA1 2-(2-Iodo-phenyl)-N-methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-acetamide; PA1 Hept-3-enoic acid methyl-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-amide; and PA1 4-Acetylamino-N-methyl-N-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-butyramide.
The compounds are disclosed as being useful as enzyme inhibitors.
U.S. Pat. No. 4,745,116 covers 2-oxy-4H-3,1-benzoxazin-4-ones, useful as serine protease inhibitors. They are represented by formula ##STR3## and the pharmaceutically acceptable acid additional salts thereof, wherein:
each R.sub.1 is independently hydrogen or lower alkyl having 1 to 6 carbon atoms, or together form a piperidine or a piperazine ring optionally substituted at the ring nitrogen by lower alkyl having 1 to 4 carbon atoms or --CH.sub.2 CH.sub.2 OH; PA2 each R.sub.2 is independently lower alkyl having 1 to 4 carbon atoms,
German Patent Number 2,315,303 covers N-substituted 2-amino-3,1-benzoxazin-4-one preparation by cyclizing 2-ureido-benzoic acids. The compounds are represented by Formula I ##STR4## where R is alkyl or aryl optionally substituted by NO.sub.2, halogen, alkyl, alkoxy, or aryloxy; R.sub.1 and R.sub.2 are H, halogen, NO.sub.2, or optionally substituted alkyl, cycloalkyl, aralkyl, aryl, alkoxy, or aryloxy is carried out by cyclizing a compound of Formula II: ##STR5## with at least an equimolar amount of a lower carboxylic anhydride dehydrating agent, optionally in the presence of an inert organic medium and/or an acid at 20.degree.-160.degree. C. The compounds are disclosed as intermediates for pharmaceuticals and plant protection agents.
The compounds of the instant invention are ortho-substituted where R is aryl substituted by halogen.
Those of the instant invention are unexpectedly better than those substituted at any other position. See Table I where Compound 4 is 3.5 .mu.M and is ortho-iodo substituted. In contrast, Compounds 5 and 6, which are meta- and para-iodo substituted, are &gt;66 .mu.M.
U.S. Pat. No. 4,315,766 covers compounds of formula, for example, ##STR6## which are disclosed as useful for control of unwanted plant growth.
U.S. Pat. No. 4,777,182 and its continuation 4,820,730 cover amidine compounds of Formula I ##STR7## and the pharmaceutically acceptable acid addition salts thereof are novel and are of use as anti-trypsin, anti-plasmin, anti-kallikrein, anti-thrombin, and anti-complement agents which may be administered orally. These amidine compounds can be produced by the reaction between a carboxylic acid compound of Formula II ##STR8## or a reactive intermediate thereof and 6-amidino-2-naphthol of Formula III ##STR9## or preferably an acid addition salt thereof.
East German Patent 286,356 teaches in part the preparation of compounds of formula ##STR10## wherein R.sub.1 is hydrogen, methyl, methoxy, or halogen and R.sub.2 is lower alkyl (C.sub.1 -C.sub.3), substituted or unsubstituted phenyl, chloromethyl, and alkoxy (C.sub.1 -C.sub.2). The compounds are disclosed as biologically active and useful as intermediates.